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Carnitine/organic cation transporter OCTN2 (Slc22a5) is responsible for renal secretion of cephaloridine in mice.
Drug Metab Dispos. 2009 May; 37(5):1009-16.DM

Abstract

Carnitine/organic cation transporter (OCTN) 2 (SLC22A5) plays a pivotal role in renal tubular reabsorption of carnitine, a vitamin-like compound, on apical membranes of proximal tubules, but its role in relation to therapeutic drugs remains to be clarified. The purpose of the present study was to elucidate the involvement of OCTN2 in renal disposition of a beta-lactam antibiotic, cephaloridine (CER), based on experiments with juvenile visceral steatosis (jvs) mice, which have a functional deficiency of the octn2 gene. Renal clearance of CER during constant intravenous infusion in wild-type mice was much higher than could be accounted for by glomerular filtration, but was decreased by increasing the infusion rate with minimal change in kidney-to-plasma concentration ratio, suggesting the existence of saturable transport mechanism(s) across the apical membranes. The plasma concentration profile and kidney-to-plasma concentration ratio after intravenous injection in jvs mice were higher than those in wild-type mice, whereas renal clearance in jvs mice was much lower than that in wild-type mice and could be accounted for by glomerular filtration. Uptake of CER by mouse OCTN2 was shown in Xenopus laevis oocytes expressing mouse OCTN2. The CER transport by OCTN2 exhibited saturation with K(m) of approximately 3 mM, which is similar to the renal CER concentration exhibiting saturation in renal clearance in vivo. The OCTN2-mediated CER transport was inhibited by carnitine and independent of Na(+) replacement in the medium. These results show OCTN2 on apical membranes of proximal tubules plays a major role in renal secretion of CER in mice.

Authors+Show Affiliations

Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakumamachi, Kanazawa 920-1192, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19220985

Citation

Kano, Takashi, et al. "Carnitine/organic Cation Transporter OCTN2 (Slc22a5) Is Responsible for Renal Secretion of Cephaloridine in Mice." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 37, no. 5, 2009, pp. 1009-16.
Kano T, Kato Y, Ito K, et al. Carnitine/organic cation transporter OCTN2 (Slc22a5) is responsible for renal secretion of cephaloridine in mice. Drug Metab Dispos. 2009;37(5):1009-16.
Kano, T., Kato, Y., Ito, K., Ogihara, T., Kubo, Y., & Tsuji, A. (2009). Carnitine/organic cation transporter OCTN2 (Slc22a5) is responsible for renal secretion of cephaloridine in mice. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 37(5), 1009-16. https://doi.org/10.1124/dmd.108.025015
Kano T, et al. Carnitine/organic Cation Transporter OCTN2 (Slc22a5) Is Responsible for Renal Secretion of Cephaloridine in Mice. Drug Metab Dispos. 2009;37(5):1009-16. PubMed PMID: 19220985.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Carnitine/organic cation transporter OCTN2 (Slc22a5) is responsible for renal secretion of cephaloridine in mice. AU - Kano,Takashi, AU - Kato,Yukio, AU - Ito,Kimihiro, AU - Ogihara,Takuo, AU - Kubo,Yoshiyuki, AU - Tsuji,Akira, Y1 - 2009/02/12/ PY - 2009/2/18/entrez PY - 2009/2/18/pubmed PY - 2009/6/23/medline SP - 1009 EP - 16 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 37 IS - 5 N2 - Carnitine/organic cation transporter (OCTN) 2 (SLC22A5) plays a pivotal role in renal tubular reabsorption of carnitine, a vitamin-like compound, on apical membranes of proximal tubules, but its role in relation to therapeutic drugs remains to be clarified. The purpose of the present study was to elucidate the involvement of OCTN2 in renal disposition of a beta-lactam antibiotic, cephaloridine (CER), based on experiments with juvenile visceral steatosis (jvs) mice, which have a functional deficiency of the octn2 gene. Renal clearance of CER during constant intravenous infusion in wild-type mice was much higher than could be accounted for by glomerular filtration, but was decreased by increasing the infusion rate with minimal change in kidney-to-plasma concentration ratio, suggesting the existence of saturable transport mechanism(s) across the apical membranes. The plasma concentration profile and kidney-to-plasma concentration ratio after intravenous injection in jvs mice were higher than those in wild-type mice, whereas renal clearance in jvs mice was much lower than that in wild-type mice and could be accounted for by glomerular filtration. Uptake of CER by mouse OCTN2 was shown in Xenopus laevis oocytes expressing mouse OCTN2. The CER transport by OCTN2 exhibited saturation with K(m) of approximately 3 mM, which is similar to the renal CER concentration exhibiting saturation in renal clearance in vivo. The OCTN2-mediated CER transport was inhibited by carnitine and independent of Na(+) replacement in the medium. These results show OCTN2 on apical membranes of proximal tubules plays a major role in renal secretion of CER in mice. SN - 1521-009X UR - https://www.unboundmedicine.com/medline/citation/19220985/Carnitine/organic_cation_transporter_OCTN2__Slc22a5__is_responsible_for_renal_secretion_of_cephaloridine_in_mice_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=19220985 DB - PRIME DP - Unbound Medicine ER -